Valsartan attenuates LPS-induced ALI by modulating NF-κB and MAPK pathways

作者全名："Zhou, Mi; Meng, Ling; He, Qinke; Ren, Chunguang; Li, Changyi"

作者地址："[Zhou, Mi; Li, Changyi] Chongqing Med Univ, Dept Resp & Crit Care, Affiliated Hosp 2, Chongqing, Peoples R China; [Zhou, Mi; Meng, Ling; He, Qinke; Ren, Chunguang] Chongqing Med Univ, Sch Basic Med Sci, Dept Cell Biol & Genet, Lab Dev Biol, Chongqing, Peoples R China"

通信作者："Li, CY (通讯作者)，Chongqing Med Univ, Dept Resp & Crit Care, Affiliated Hosp 2, Chongqing, Peoples R China.; Ren, CG (通讯作者)，Chongqing Med Univ, Sch Basic Med Sci, Dept Cell Biol & Genet, Lab Dev Biol, Chongqing, Peoples R China."

来源：FRONTIERS IN PHARMACOLOGY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001152514100001

JCR分区：Q1

影响因子：5.6

年份：2024

卷号：15

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：valsartan; acute lung injury; LPS; MAPK; NF-kappa B

摘要："Background: Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common respiratory disease characterized by persistent hypoxemia and an uncontrolled inflammatory response. Valsartan, an angiotensin II type 1 receptor antagonist, is clinically used to treat hypertension and has anti-inflammatory and antioxidant effects on gefitinib-induced pneumonia in rats. However, the potential therapeutic effects of valsartan on lipopolysaccharide (LPS)-induced ALI remain unclear. This study investigated the protective role of valsartan in LPS-induced ALI and its underlying mechanisms. Methods: LPS-treated BEAS-2B cells and ALI mouse model were established. BEAS-2B cells were treated with LPS (10 mu g/mL) for 24h, with or without valsartan (20, 40, and 80 mu M). For ALI mouse models, LPS (5 mg/kg) was administered through intratracheal injection to treat the mice for 24h, and valsartan (10 or 30 mg/kg) was injected intraperitoneally twice 2 h before and 12 h after the LPS injection. Pulmonary functional parameters were examined by an EMKA pulmonary system. Hematoxylin and eosin staining, flow cytometry, CCK-8 assay, qRT-PCR, ELISA, immunofluorescence, Western blotting, and related commercial kits were used to assess the pathological damage to the lungs, neutrophil recruitment in the lung tissue and bronchoalveolar lavage fluid (BALF), cell viability, inflammation, oxidative activity, and mucus production, respectively. Potential mechanisms were further explored using network pharmacology and Western blotting. Results: Valsartan rescued LPS-reduced cell viability of BEAS-2B cells, improved the pulmonary function, ameliorated pathological lung injury in mice with ALI, ameliorated LPS-induced neutrophil recruitment in BALF and lung tissue of mice, attenuated oxidative stress by increasing the level of SOD and decreasing that of MDA and GSSG, inhibited LPS-induced MUC5AC overproduction, decreased the LPS-induced increase in expression of pro-inflammatory cytokines/chemokines including TNF-alpha, IL-6, IL-1 beta, CXCL-1 and CXCL-2, and restored the expression of anti-inflammatory IL-10. Mechanistic studies showed that valsartan inhibits LPS-induced phosphorylation of nuclear factor-kappa B (NF-kappa Beta) and mitogen-activated protein kinases (MAPKs) including P38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) in both LPS-treated cells and the mouse model of ALI. Conclusion: Valsartan protects against LPS-induced ALI by attenuating oxidative stress, reducing MUC5AC production, and attenuating the inflammatory response that may involve MAPK and NF-kappa Beta pathways."

基金机构：Chongqing Municipal Science and Technology Bureau10.13039/501100002865

基金资助正文：We would like to thank Luo Ren and Juan Li at the Children's Affiliated Hospital of Chongqing Medical University for the assiatance of lung function measurement.